Mast cells play central roles in varied inflammatory reactions due to their ability to release a diverse array of biologically active factors. During the last decade, the primary focus has been on the role of mast cell-derived histamine, leukotrienes, prostaglandins, cytokines, and chemokines in inflammation. Little attention has been paid to the role of tryptases even though these serine proteases are major constituents of the secretory granules of human, mouse, rat, gerbil, and dog mast cells. Accordingly, the mechanisms by which mast cell tryptases mediate inflammation have not been identified.
All mast cell proteases are targeted to the secretory granule as inactive zymogens but they are rapidly activated at this site. Thus, they are stored in the granule in their mature, enzymatically active forms. Tryptases, the major secretory granule proteases of human mast cells, are glycosylated, heparin-associated tetramers of heterogenous, catalytically active subunits. These enzymes are stored in an enzymatically inactive state in the mast cell's secretory granules and are released from the cell following activation through the high affinity IgE receptor. Tryptases have been implicated in a variety of biological processes including tissue inflammation.
Various attempts have been made to identify inhibitors of tryptase for treating inflammatory disorders. For example, small aromatic molecules have been proposed as tryptase inhibitors for preventing and treating inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis. (See, e.g., U.S. Pat. No. 5,525,623, issued to Spear et al., "Compositions and Methods for the Treatment of Immunomediated Inflammatory Disorders"; and International Application Nos. PCT/US95/11814, WO96/09297, and PCT/US94/02706, WO94/20527, Applicant: Arris Pharmaceutical Corporation.) Unfortunately, such molecules nonspecifically inhibit a variety of serine proteases (including pancreatic trypsin) that are present in vivo and, accordingly, the therapeutic value of such molecules for treating conditions mediated by mast cell tryptase remains questionable.
In view of the demonstrated involvement of mast cells in the initiation of inflammation, a need still exists to understand the mechanisms by which mast cells control such inflammation and to develop new and useful agents that inhibit or prevent inflammation in the first instance. Preferably, such agents would selectively inhibit specific components produced by the mast cell that are responsible for the inflammation, thereby requiring administration of relatively low doses of the agent and minimizing the likelihood of side reactions that may be associated with the administration of a high dosage of the agent.